Received for publication January 24, 2006.
Revised March 20, 2006.
Accepted for publication March 20, 2006.

Anti-amnesic and neuroprotective effects of donepezil against learning impairments induced in mice by exposure to carbon monoxide (CO) gas

Abstract

Donepezil is a potent acetylcholinesterase inhibitor that also interacts with the sigma₁ (₁) receptor, an intracellular neuromodulatory protein. In the present study, we analyzed the anti-amnesic and neuroprotective activities of donepezil in a mouse hypoxia model induced by repetitive CO exposure, comparing donepezil's pharmacological profile with other cholinesterase inhibitors tacrine, rivastigmine and galanthamine, and the reference ₁ agonist igmesine. CO-exposure induced, after 7 days, hippocampal neurodegeneration, analyzed by Cresyl violet staining, and behavioral alterations, measured using spontaneous alternation and passive avoidance responses. When injected 20 min before the behavioral tests, i.e. 7-8 days after CO, all drugs showed anti-amnesic properties. Pre-administration of the ₁ receptor antagonist BD1047 blocked only the igmesine and donepezil effects. The neuroprotective activity of the drugs was tested by injection 20 min before the first CO-exposure (pre-insult protection) or by injection 1 h after the last CO-exposure (post-insult protection). All drugs alleviated the hypoxia-induced neurodegeneration and behavioral impairments when injected before CO-exposure. Pre-administration of BD1047 blocked both the igmesine and donepezil effects. However, when injected after CO-exposure, only igmesine and donepezil induced effective neuroprotection and the morphological and behavioral effects were BD1047-sensitive. These results showed that donepezil is a potent anti-amnesic and neuroprotective compound against the neurodegeneration induced by excitotoxic insult and its pharmacological actions as both an acetylcholinesterase inhibitor and ₁ receptor agonist contribute to its marked efficacy. In particular, the drug is a more potent post-insult protecting agent as compared to more selective cholinesterase inhibitors.

Key words: CO exposure, amnesia, cholinesterase inhibitor, hypoxia, neuroprotection, sigma-1 receptor

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